Cord Blood Hematopoietic Cell Transplantation Research Articles

Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia In Patients up to Age 75: Comparison of Survival In Patients with An Available Donor Compared to Patients without a Donor

AbstractAbstract 2381Allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment strategy for patients with Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML). Recent reduction of the transplant related toxicity has permitted the expansion of empiric age limitations for HCT up to 75 years. There has been limited comparative data on HCT focusing on donor availability in patients with MDS/CMML. Between January 2004 and September 2009, a total of 255 new patients (NP) with a diagnosis of MDS or CMML were evaluated for HCT at Moffitt Cancer Center. This report describes the outcomes of these patients with emphasis on donor availability. Donor Search Results: Of the 255 NP, 58 did not undergo a donor search. Reasons for not proceeding were as follows: Medicare declined coverage due to age >65 (18), waiting as have low risk disease (15), patient declined (6), patient seen as second opinion only (7) and patient was not eligible for HCT (12). These patients were not included in the survival analysis. Of the 197 patients who had a donor search initiated, a sibling (SIB) matched unrelated (MUD) or single HLA antigen/allele mismatch (mMUD) unrelated adult donor was found in 173 patients. A suitable adult donor was not identified in the remaining 24 patients. To mitigate bias due to factors giving a survival advantage to patients who were stable enough to survive the donor and proceed to HCT, the survival analysis included only those patients alive 90 days after the donor search was initiated. We have been able to identify donors within this time frame for 99% of the patients who ever found one, although time to transplant is longer. At the 90 days landmark, there were 164 patient in the Donor cohort, and 19 patients in the No Donor cohort. Donor Cohort: The median age was 56.6 yrs (18.5 – 73.5). Ninety-seven patients (59%) were older than 55 yrs and 26 (16%) were above 65 yrs. At the time of the transplant consult, IPSS risk was Low (10), Int-1 (44), Int-2 (48), High (25), AML (21), CMML (13), or not evaluable (NE) (3). Donors included SIB (60), MUD (75) and mMUD (29). Median follow-up of surviving patients is 27.7months (7.2 – 70.7). No Donor Cohort: Median age was 57.4 yrs (32.6 – 68.1) with 12 patients (63%) older than 55 yrs and 3 (16%) patients older than 65 years of age. IPSS at initiation of the donor search was Int-1 (5), Int-2 (6), High (5), AML (1) and CMML (2). Median follow-up is 9.2 months (1.4 – 61.5). Of the 19 patients with no donor, 3 patients received an umbilical cord blood HCT elsewhere and were analyzed by intent to treat. Outcomes: Patients with a donor had significantly improved overall survival from time of donor search vs. patients with no donor (P=0.007) with 2 year OS of 48% vs. 23%, respectively. Median survival for the donor group was 22.2 months [95% CI 14.7 – 35.7] vs. 10.1 months for those without a donor [95% CI 2.3 – 14.7]. Transplant: Of the 164 patients with a donor, 121 (74%) patients received the planned allogenic transplants. The 2-year overall survival (OS) after transplantation is similar for SIB (51%), MUD (39%) or mMUD (68%) transplant recipients (P=0.4), and also similar by age below or above 55 years (P=0.7). These data demonstrate that most patients with MDS or CMML can have a suitable donor identified and proceed to HCT. Overall survival is significantly improved for those patients who have a suitable sibling or unrelated donor. Disclosures:Lancet: Eisai: Consultancy; Celgene: Honoraria. Alsina: Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. List: Celgene: Research Funding.

The World Marrow Donor Association: 20 years of international collaboration for the support of unrelated donor and cord blood hematopoietic cell transplantation

The transplantation of hematopoietic stem cells from unrelated volunteer donors and cord blood units is made possible through an international collaboration of registries and cord blood banks. The World Marrow Donor Association (WMDA) is a non-profit association based in Leiden, The Netherlands, whose mission it is to assure that high quality stem cell products are available for all patients in need, while maintaining the health and safety of the volunteer donors, This goal is accomplished through the work of six working groups and six board committees, in which issues of global significance to the clinical hematopoietic cell transplantation community are identified and guidelines are established. In this special issue of Bone Marrow Transplantation, the activities of the WMDA and a vision for future directions in the field are presented.

Obesity Does Not Preclude Safe and Effective Myeloablative Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML) in Adults

INTRODUCTION: Obesity is increasingly common in the US and is frequently associated with co-morbid medical conditions that may increase the risk of HCT, often the optimal treatment for AML. HCT risk and outcomes for AML on the basis of body mass index (BMI) have not been well-characterized. Using data from the Center for International Blood and Marrow Transplant Research (CIBMTR), we have previously shown no significant difference in outcomes for autologous HCT for lymphoma among normal weight, overweight, and obese patients (pts) but worse outcomes for underweight pts (Navarro et al, BBMT 2006, 12(5): 541–51). Here, we compare outcomes by weight groups for AML patients who underwent autologous, related, or unrelated HCT.METHODS: Our final population included patients age ≥ 18 who underwent myeloablative unpurged autologous or allogeneic HCT for AML in 1st or 2nd complete remission, primary induction failure, or 1st relapse reported to the CIBMTR from 1995 to 2004. Cord blood HCTs were excluded. Four weight groups were defined based on BMI (BMI=weight (kg)/ height (m2)): underweight <18; normal=18–25; overweight >25–30; and obese >30. Treatment-related mortality (TRM), relapse, leukemia-free survival (LFS), and overall survival (OS) were compared using multivariable proportional hazards regression analysis accounting for patient, disease and HCT-related variables.RESULTS: We included 373 autologous, 2041 related, and 1801 unrelated transplant recipients. Patient-, disease-, and transplant characteristics were well-matched across weight groups and transplant types. Multivariable analysis examining risks (95% confidence intervals) relative to the normal weight group are:HCT TypeNormalUnderweightOverweightObeseAutologousn=164n=5n=112n=81Death–NSNSTreatment failure–NSNSRelapse–NSNSTRM–NSNSRelated Allogeneicn=1161n=31n=543n=268Death1.86 (1.24–2.78)NS1.23 (1.04–1.47)Treatment failure2.08 (1.37–3.15)NS1.19 (1.00–1.42)Relapse2.02 (1.18–3.47)NSNSTRM2.22 (1.17–4.22)NS1.32 (1.02–1.70)Unrelated Allogeneicn=846n=31n=523n=368DeathNSNSNSTreatment failureNSNSNSRelapseNS0.82 (0.68–0.99)0.76 (0.60–0.96)TRMNSNSNS– =not done due to insufficient number of pts; NS=not significant; treatment failure = death or recurrence of disease.CONCLUSIONS: There were no significant differences in risk of TRM, LFS, relapse or OS for normal weight, overweight or obese patient groups who received autologous HCT. Obese recipients of related HCT for AML had increased risk of death, treatment failure, and TRM, though the magnitude was small, an effect was not seen in the unrelated HCT group. Underweight patients who received a related, but not unrelated HCT, fared substantially worse than normal weight patients for all outcomes. It may be that the higher risk of the unrelated HCT procedure masks important but less obvious risks associated with being underweight whereas in the related donor HCT setting, such risks become manifest. Small numbers of patients limit the ability to better characterize this finding in underweight patients. Disproportionately, fewer transplants have been reported in underweight patients which suggest they experience disease and patient-related factors that preclude transplantation. No differences were observed for incidence of acute or chronic GVHD for any weight group. Overweight and obesity should not be a barrier to HCT; however, caution should be exercised in selecting underweight patients for HCT.

Glutathione S‐Transferase A1 Genetic Variants Reduce Busulfan Clearance in Children Undergoing Hematopoietic Cell Transplantation

The effect of glutathione S-transferase variants on pediatric busulfan metabolism was investigated by noncompartmental and population pharmacokinetic modeling. Twenty-nine children who underwent related or unrelated bone marrow or umbilical cord blood hematopoietic cell transplant were retrospectively studied. GSTA1, GSTP1, and GSTM1 variants were explored for their effects on busulfan exposures. Noncompartmental pharmacokinetic analyses showed that carriers of GSTA1*B had a 2.6-fold higher busulfan area under the curve and concentration at steady state compared with noncarriers (P <or= .01). Population pharmacokinetic modeling demonstrated that carriers of GSTA1*B reduced busulfan clearance by 30%. Monte Carlo simulations were then performed to assess busulfan dosing regimens based on GSTA1 genotypes. Simulations determined that dosing based on GSTA1 genotype, weight, and age resulted in fewer children exceeding the upper therapeutic limit compared with dosing using age and weight only. Larger, prospective studies are needed to confirm these findings.

3: Reduced Intensity (RI) aLlogeneic Cord Blood Hematopoietic Cell Transplantation (Allo-CBHCT) in Pediatric Patients with Malignant and Non-Malignant Diseases

3: Reduced Intensity (RI) aLlogeneic Cord Blood Hematopoietic Cell Transplantation (Allo-CBHCT) in Pediatric Patients with Malignant and Non-Malignant Diseases

Reduced intensity (RI) allogeneic cord blood hematopoietic cell transplantation (Allo CBHCT) in pediatric patients with malignant and non-malignant diseases

Reduced intensity (RI) allogeneic cord blood hematopoietic cell transplantation (Allo CBHCT) in pediatric patients with malignant and non-malignant diseases

Reduced Intensity (RI) Allogeneic Cord Blood Hematopoietic Cell Transplantation (Allo CBHCT) in Pediatric Patients with Malignant and Non-Malignant Diseases.

We and others have demonstrated that cord blood hematopoietic cells can be used successfully as an alternative allogeneic progenitor cell source in pediatric and adult recipients with both malignant and non-malignant diseases (Cairo et al, Blood 1997). However, there is significant amount of morbidity and mortality following myeloablative CBHCT (Gluckman et al, NEJM 1997; Rubinstein et al, NEJM 1998). RI conditioning may potentially reduce the incidence of regimen-related mortality (RRM) and the late effects associated with myeloablative regimens without increasing the risk of graft failure or relapse in children and adolescents (Del Toro et al, BMT 2004). Successful engraftment has been demonstrated in adult recipients with advanced hematologic malignancies who received unrelated mismatched cord blood following RI conditioning regimens (Chao et al, BBMT 2004). We report the results in 22 pediatric recipients, 6F:16M, median age 6.5 years (0.4–21). Twenty-one received unrelated CBHC, the majority mismatched at 1–2 HLA-Loci, 4/6 (n=14), 5/6 (n=5), 6/6 (n=2); 1 sibling CBHC (6/6). Recipients were transplanted for malignant n=17, [HD (5), NHL (2), NB(4),AML (2), MDS(3),CML (1)] and non-malignant n=5, [b-thal (1), HLH (2), WAS (1), SCD(1)] diseases. Poor-risk disease was defined as induction failure, PD, SD, ≥CR3, and 2nd allo HCT (n=8). RI conditioning was fludarabine-based (150–180mg/m2) with either busulfan (8mg/kg) +/− rabbit ATG/alemtuzumab or cyclophosphamide +/− etoposide/etoposide phosphate +/− ATG and craniospinal radiation prophylaxis (n=1). Graft-vs.-host-disease (GHVD) prophylaxis: tacrolimus 0.03 mg/kg/day and mycophenolate mofetil 900mg/m2 q 6h (Osunkwo et al, BBMT 2004). Median total nucleated cell count was 3.8 x107/kg (0.92–10.82) and CD34 cell count was 2.2 x105/kg (0.34–6.95). The median day to neutrophil engraftment was 19.5 days (1–47) and to platelet engraftment was 40 days (6–170). Engraftment was 72.7%. There were 6 primary graft failures observed (1 CML, 1 b-Thal, 2 HLH, 1 MDS, and 1 AML). Within this subgroup of graft failures, 4 were regrafted with myeloablative conditioning followed by a second CBHCT and 100% engrafted. Of the 16 engrafted patients, 15 achieved 90% or greater mixed-donor chimerism by day 60. Five of 16 evaluable patients developed acute GVHD, with 3 of those 5 developing grade III/IV acute GVHD. One patient developed extensive chronic GVHD. There were 8 deaths (4 PD, 1RRM, 3 GVHD). The probability of 3-year overall survival (OS) in all patients was 61%. Despite a log less nucleated cells/kg with CB vs. PB or BM HCT, the 3-yr OS in standard-risk malignancy pts. was 90%. The 1-yr OS in poor-risk malignancy pts. was 21%. The 1-yr OS in non-malignant diseases was 75%.These preliminary results indicate that RI Allo CBHCT may result in more rapid hematopoietic reconstitution while decreasing RRM compared to myeloablative CBHCT and be associated with high-to-full mixed-donor chimerism. Patients with diseases such as CML, β-Thal, and HLH may require increased intensity of conditioning. Further follow-up is required to evaluate the difference, if any, in long-term effects following RI Allo CBHCT.